Vilar Marçal, Chou Hui-Ting, Lührs Thorsten, Maji Samir K, Riek-Loher Dominique, Verel Rene, Manning Gerard, Stahlberg Henning, Riek Roland
The Salk Institute for Biological Studies, North Torrey Pines Road, La Jolla, CA 92037, USA.
Proc Natl Acad Sci U S A. 2008 Jun 24;105(25):8637-42. doi: 10.1073/pnas.0712179105. Epub 2008 Jun 12.
The aggregation of proteins into amyloid fibrils is associated with several neurodegenerative diseases. In Parkinson's disease it is believed that the aggregation of alpha-synuclein (alpha-syn) from monomers by intermediates into amyloid fibrils is the toxic disease-causative mechanism. Here, we studied the structure of alpha-syn in its amyloid state by using various biophysical approaches. Quenched hydrogen/deuterium exchange NMR spectroscopy identified five beta-strands within the fibril core comprising residues 35-96 and solid-state NMR data from amyloid fibrils comprising the fibril core residues 30-110 confirmed the presence of beta-sheet secondary structure. The data suggest that beta1-strand interacts with beta2, beta2 with beta3, beta3 with beta4, and beta4 with beta5. High-resolution cryoelectron microscopy revealed the protofilament boundaries of approximately 2 x 3.5 nm. Based on the combination of these data and published structural studies, a fold of alpha-syn in the fibrils is proposed and discussed.
蛋白质聚集成淀粉样纤维与几种神经退行性疾病有关。在帕金森病中，人们认为α-突触核蛋白（α-syn）从单体通过中间体聚集成淀粉样纤维是致病的毒性机制。在这里，我们使用各种生物物理方法研究了处于淀粉样状态的α-syn的结构。淬灭氢/氘交换核磁共振光谱确定了纤维核心内包含35-96位残基的五条β链，来自包含30-110位纤维核心残基的淀粉样纤维的固态核磁共振数据证实了β折叠二级结构的存在。数据表明β1链与β2相互作用，β2与β3相互作用，β3与β4相互作用，β4与β5相互作用。高分辨率冷冻电子显微镜揭示了约2×3.5nm的原纤维边界。基于这些数据和已发表的结构研究的结合，提出并讨论了α-syn在纤维中的折叠情况。
